Amine salts of pyrrolidone carboxylic acid



United States Patent 3,255,190 AMINE SALTS 0F PYRRQLIDONE CARBOXYLICAilil) Robert H. Broh-Kahn, Hastings on Hudson, Alfred Halpern, LakeSuccess, and Ernest J. Sasmor, Yonkers, N.Y., assignors to Laboratoriesfor Pharmaceutical Development, Inc., Yonkers, N.Y., a corporation ofNew York No Drawing. Filed May 31, 1961, Ser. No. 113,649

6 Claims. (Cl. 260-2472) This invention relates to novel therapeuticcompounds derived from pyrrolidone carboxylic acid and an organic amine,which exert a beneficial effect in the treatment of the alcoholicpatient, the elderly chronically ill patient with deteriorated mentalfunction, and the patient with generalized psychologic depressionarising from a multiplicity of causes, chiefly associated withanxiety-tension. In particular, this invention relates to the aminesalts of pyrrolidone carboxylic acid, as for example, cholinepyrrolidone carboxylate, betaine pyrrolidone carboxylate, morpholinepyrrolidone carboxylate, methenarnine pyrrolidone carboxylate, andpiperazine pyrrolidone carboxylate, their method of manufacture,therapeutic compositions comprising the said compounds and apharmaceutically acceptable carrier and a method of obtaining anelevated blood level of glutamic acid by the administration of thesecompounds.

Although medical advances have led to an appreciable increase in theaverage life-span, paradoxically this has resulted in an increasednumber of problems pertaining to care of the aged. It is known that themental status tends to deteriorate more rapidly than does the physicalcondition and with an increased number of individuals living longer,psychologic deterioration is observed more frequently than before. Themany problems arising in the course of everyday living in modernsociety, all too frequently induce a state of psychologicdisorientation, re

sulting in apathy and depression. Consequently, more and more agedindividuals are being channeled into specialized institutions for thecare which they require and the treatment of these individuals hascreated a most pressing problem for modem-day medicine.

In the past very little benefit could be provided to these individualsand recently much interest has been given to the problem of devising newtherapeutic modalities which would enhance mental functioning of thesepatients so as to restore them as useful, creative members of society.

Among the modalities studied was pentylenetetrazole, a potent convulsivecompound, which was intended to produce a beneficial eifect throughstimulation of the central nervous system. It was soon found that thisdrug must be used at its toxic level and the frequency with whichconvulsions were produced soon led to the discarding of this preparationfor routine usage. When pentylenetetrazole was used at lower and saferdosages, the beneficial effects which have been described for it werenot observed.

The use of sympathomimetic stimulants, such as amphetamine and relatedcompounds, is not desirable because of the concurrent state of agitationwhich is produced by these compounds. Furthermore, the generalizedstimulation of the overall sympathetic nervous system is undesirable fortherapy intended for long periods of time in patients who are prone todebilitating diseases. Recent years have witnessed a new approach to thesupport of failing functioning of the brain cell through the use ofessential metabolites, thereby supporting the deteriorating systems at acellular level. Glutamic acid is such an essential metabolite which hasbeen found to exert a beneficial elfect on the mental functioning of thepatient. It has been shown that glutamic acid is found in highconcentration in brain tissue with approximately times greater amountspresent than are other amino acids essential to normalized functioningof the brain cell. Clinical study of glutamic acid has revealed that itis capable of exerting a beneficial psychotonic effect, if administeredin large quantity and for prolonged periods of time. This necessity forelevated levels of dosage administration results from its insolubilityin tissue fluids and consequent limited absorption. Furthermore, evenafter absorption into the blood stream, glutamic acid does not penetrateacross the blood-brain barrier, which is necessary if it is to exert abeneficial effect on cerebrocellular metabolism.

These inherent limitations of glutamic acid therapy have led to manyattempts at their correction but with little success. Among the meansused to improve the absorption rate of glutamic acid is the conversionof the acid to the sodium salt, but it was soon demonstrated that thisdid little to effect passage across the blood-brain barrier.

Furthermore, the administration of the large amounts of the sodium saltof glutamic acid may result in disturbances of the acid-base balance ofthe blood, as well as affecting water retention, particularly inpatients with cardiac disease. The use of special solubilizing agentshas. similarly failed in this connection.

Pyrrolidone carboxylic acid is pyrogenetically derived from glutamicacid by loss of Water. The resultant compound is capable of exerting asimilar physiologic elfect as glutamic acid, either by entering into thesame enzyme reactions or by being converted into glutamic acid at thecellular level. 7

However, unless pyrrolidone carboxylic acid is protected, it is rapidlyconverted to glutamic acid by hydration and the compound now assumes allof the inherent limitations of the older glutamic acid.

In contrast to this, the products of the present invention arestabilized so that the hydration of pyrrolidone carboxylic acid toglutamic acid in the presence of physiologic fluids is virtuallyeliminated and the compound is capable of exerting its salutory,pharmacodynamic action at the cellular level. This is established by thetransfer across the blood-brain barrier. This further establishes theimproved absorption and physiologic utilization of pyrrolidonecarboxylic acid in contrast to the older glutamic acid.

Furthermore, through the administration of the amine salts ofpyrrolidone carboxylic acid, a more convenient therapy is available,since the compound does not have the disagreeable taste of glutamic acidand may be administered less frequently and in smaller dosage regimens.

The amine salts of pyrrolidone carboxylic acid are obtained through theinter-reaction between the appropriate amine and pyrrolidone carboxylicacid. Since pyrrolidone carboxylic acid has a high degradation rate, thefreshly prepared acid is neutralized with the selected amine in an inertmedium. When conducting this reaction, it is preferred that an excess ofpyrrolidone carboxylic acid is present until the pH break-point isreached, after which a slight excess of the amine is desired. The excessof amine present during the latter phases of the reaction is from 0.1 to0.5 percent.

In carrying out the reaction, the freshly prepared pyrrolidonecarboxylic acid is dissolved in an inert medium, as for example, butylalcohol, and to this is added, in small increments, a solution of theselected amine, dissolved in the same solvent. The pH of the solution isdetermined after each increment is added. When the pH break-point isreached, the concentration of amine is increased slightly to maintainthe described excesses.

After the reaction has been completed, the resultant compound may beused for further manufacturing steps of the final dosage form; or it maybe isolated and purified. An outstanding advantage of these compounds istheir increased solubility in aqueous or physiologic fluids,

The unit dosage range of concentration of active material for thetablet, may be as high as 0.75 gram of active substance. However, itwill be found preferable to utilize a smaller concentration and 500mgms. of active ingredient per tablet is an optimal concentration.

The granulated mix, prior to the addition of a lubricant, may beutilized for the preparation of capsules, or, the

TABLE I.PHYSICAL-CHEMICAL PROPERTIES OF THE AMINE SALTS OF PYRROLIDONECARBOXYLIC ACID Elemental Analysis Amine salt Enipiric M.W. M.P., 0.Percent Percent Percent formula Carbon Hydrogen Nitrogen Thry. Fnd.Thry. Fnd. Thry. Fnd.

Betnine CmHnNzO5 245. 3 128-130 48. 97 48. 83 6. 99 7.02 11. 42 11. 31Choline (31011 232. 3 A 51. 70 49.12 8. 68 7.14 12.06 11. 01 McthemmineC1iH1sN O 268. 3 204 (dec.) 49. 24 49. 31 6.76 6. 66 26.11 26. 23Morpholine CnHN:Oi 215. 2 105-106 50. 22 50. 81 7. 02 T. 12 13. 02 13.26 Piperazine CQI'I15N303 214. 2 181-183 50. 45 51.01 7. 53 7. 8G 19. 6219. 41

Thry.=thcory; Fnd.=found.

AClt0line pyrrolidone carboxylic acid is a semi-solid compound at roomtemperature.

When it is desired to utilize the amine salts of pyrrolidone carboxylicacid in therapy, they may be administered orally as a solution, tabletcapsule or powder or parenterally by intramuscular or intravenousinjection. When oral administration is utilized, the daily dosage rangeis from 1 gram to 15 grams per day depending upon the individual patientneeds. The particular dosage-form used may then be administered toprovide the total daily dosage selected for the particular patient. Whenthese agents are intended for parenteral administration, they may beadministered intravenously by the continuous slow-drip technique or bymultiple injections either intravenously or intramuscularly. A preferredtechnique is by slow intravenous drip. The active ingredient, previouslydissolved in water-for-injection, under an aseptic technique andsterilized, is added to the intravenous drip solution so that thetotaldaily dose is provided in a slow, continuous manner.

Both routes of administration have been found useful in treatingpsychologic depression associated with senility and also to support thefailing cerebral function. These techniques have also proven of value intreating the alcoholic patient and beneficial effects have beendemonstrated by a decrease in the serum gamma-globulin fraction of bloodof the alcoholic patient. It is well known that in alcoholics,disturbances of the gamma-globulin fraction of the blood are common, dueto disturbed liver function. Thus, by the administration of cholinepyrrolidone carboxylate, or betaine pyrrolidone carboxylate, or mixturesof these, a prompt return to normal level of the serum gamma-globulinfraction of the alcoholic patient is observed, at the same time thatcerebral cellular function is augmented.

Still another desirable pharmacologic property is observed when thesecompounds are administered to an agitated patient in that it facilitatesthe tranquilization of the patient without the super-imposition ofnoxious side reactions, such as addiction, as with opiate andbarbiturates or nausea and vomiting and convulsions.

The amine salts of pyrrolidone carboxylic acid may be formulated intotablets by mixing the selected compound with a diluent in a ratio of 1part active compound to from 0.25 to 9 parts of diluent. The diluent tobe used may be lactose, sucrose, corn starch or potato starch. Afterthorough mixing, the whole is wetted with a granulating solution, as forexample, 5% gelatin solution, 2% tragacanth solution or 1% acaciasolution, and the wetted mass passed through a No. 16 coarse sieve. Thegranulated mass is then dried and mixed with a lubricant, as forexample,magnesium stearate. The amount of lubricant required depends upon thetotal mass and generally a range of from 0.1 to 0.25 gram will besufficient. After thorough mixing, the granulation is then compoundedinto tablets by compression.

pure active ingredient may be filled directly into the capsule. In thepreparation of capsules, the amount of active ingredient which isutilized for each unit dose ranges from 0.1 gram to 1.0 gram.

The active ingredient may also be dispensed in the form of a powder orgranulation. When the powder is utilized, the active ingredient is mixeddirectly with a diluent in a ratio of from 1 part active ingredient to 1part diluent, to 1 part active ingredient to 14 parts diluent. Diluentssuch as sucrose, lactose, mannitol, corn starch, potato starch, andmixtures of these may be utilized.

In order to prepare granules, the mixture is then wetted with apharmaceutically acceptable granulating solution, such as 5% gelatinsolution, 2% tragacanth solution, or 1% acacia solution, and the masspassed through a coarse sieve with a No. 8 screen.

After the primary granulation, the granules are mixed with suitablecoloring and flavoring, as for example, volatile oils and artificialsweeteners, and the entire mass regranulated through a No. 8 screen. Thepowder or granules are dispensed so that an individual unit dose (ateaspoonful or a tablespoonful), contains from 0.5 gram to 3 grams ofthe active ingredient.

A particular therapeutic advantage of the amine salts of pyrrolidonecarboxylic acid is their dramatically increased solubility in aqueousmedia. This property facilitates the utilization of the compound inliquid dose-form. Thus, by the simple dissolution of the activeingredient in a pharmaceutically acceptable carrier, such as water, smple syrup, alcohol, glycerine, propylene glycol or combinations ofthese, a liquid preparation is obtained, which permits the convenientadministration of the daily dosage of the active material, to thepatient. Furthermore, the liquid dose-forms are particularlyadvantageous for administration of the active compound for thosepatients who cannot swallow tablets or capsules. The range inconcentration of the active material in the liquid dose-form is adjustedso that the individual unit dose (teaspoonful or tablespoonful) willcontain from 1 gram to 5 grams of the active compound. Suitableflavoring and coloring may be added, if desired, to the liquidpreparations. concentrate of the active compound in water-for-inectionis prepared so that each cc. contains at least 1 gram of the activesubstance. This concentrate may then be diluted further withwater-for-injection for direct intravenous or intramuscularadministration or added to the continuous intravenous infusion drip, toprovide a daily dose by parenteral administration. The aqueousconcentration is of particular advantage in administering the productsof the present invention to those patients who are being fedintravenously and who require the special, beneficial pharmacodynamiceffects afiorded by these compounds.

Example 1 Pyrrolidone carboxylic acid is prepared by autoclaving asuspension of glutamic acid inan equal weight of water for 3 to '5 hoursat 135 C. to 140 C., after which time, the warm solution is decolorizedwith activated charcoal; filtered and cooled. Pyrrolidone carboxylicacid precipitates as a white solid which is separated from the motherliquor by filtration. The compound may be re-crystallized from butylalcohol or acetone and dried if desired.- The dried pyrrolidonecarboxylic acid melts at 160 C.

In a three-neck, round-bottom glass boiling flask, fitted with a refluxcondenser, a stirrer and a dropping funnel, is placed a solution of onemol of freshly prepared pyrrolidone carboxylic acid, dissolved in oneliter of n-butyl alcohol. The stirring is started and the solutionheated to a temperature of about 80 C. and one mol of a 33% aqueoussolution of choline bicarbonate is added, dropwise. There is animmediate ebullition of carbon dioxide gas as the reaction takes place.When about three-fourths of the quantity of choline bicarbonate has beenintroduced into the reaction mixture, the pH of the solution isdetermined and plotted against concentration of amine added. The pH ofthe solution is then carefully controlled, so that it never rises abovepH 7. After all of the choline bicarbonate has been added, the mixtureis allowed to cool to room temperature and the solvent removed underreduced pressure (0.2 mm. Hg). The residue may be further purified bydissolving in acetone and recovering the compound. The resultantcompound is semi-solid, has a molecular weight of 232.3 and contains44.86 percent choline and 55.4 percent of pyrrolidone carboxylic acid.Choline pyrrolidone carboxylate analyzes in good agreement with itstheoretical values for carbon, hydrogen and nitrogen.

Theory: Percent carbon, 51.70; percent hydrogen, 8.68; percent nitrogen,12.06. Found: Percent carbon, 49.12; percent hydrogen, 7.14; percentnitrogen, 11.01.

The compound is very soluble in water, alcohol, propylene glycol,glycerine and sorbitol; slightly soluble in acetone and insoluble inchloroform.

Example 2 In place of the choline bicarbonate used in Example I above,'may be substituted a stoichiometric equivalent quantity of betainebicarbonate morpholine bicarbonate, piperazine bicarbonate ormenthenamine bicarbonate. The remainder of the steps are the same andthe compound resulting will be the respective salt of pyrrolidonecarboxylic acid of selected amine bicarbonate used, having the followingproperties:

pyrrolidone carboxylate.

6 Example 3 One mol of freshly prepared pyrrolidone carboxylic acid isdissolved in one liter of isopropyl alcohol and to it is added asolution of onemol of betaine dissolved in one-half liter of isopropylalcohol. When all of the betaine has been added, the solvent is removedby distillation and the residue recovered. The residue is betaineBetaine pyrrolidone carboxylate is a white crystalline solid melting at128 C. to 130 C., and is very soluble in water, slightly soluble inallcohol and acetone and insoluble in chloroform. It analyzes in goodagreement with its calculated theoretical values for percent carbon,hydrogen and nitrogen.

Theory: Percent carbon, 48.97; percent hydrogen, 6.99; percent nitrogen,11.42. Found: Percent carbon, 48.83; percent hydrogen, 7.02; percentnitrogen, 11.31.

Example 4 In place of betaine used in Example 3, may be substituted astoichiometric equivalent quantity of choline, methenamine, morpholineor piperazine. The remainder of the steps being the same as described.The respective amine salts of pyrrolidone carboxylic acid are obtained,which have identical properties to those described in Example 2 above.

Example 5 In place of the butyl alcohol. and isopropyl alcohol used inExamples 1 through 4, may be substituted any liquid alcohol of the classROH, wherein R is a straight or branched alkyl chain of from 1 to 6carbons.

Water may be used to replace the alcohols used as a solvent in Examples1 through 4, either wholly or in part. When water is used to dilute thealcohols used as a solvent it may be utilized in concentration of fromone percent to 99 percent by weight. When water is used as a solvent,the final reaction product need not be isolated but the evaporation ofthe water may be carried to the point Where the concentration of activecompound per cc. is that desired to be used in therapy. In this instancethe flavoring and other components desired for the final formulation maybe added to the solution of the selected amine salt of the pyrrolidonecarboxylic acid.

When'a liquid amine, such as morpholine is used as the reactant, nosolvent is necessary. A huge excess, as for example, a 5 molar excess isused, and the additional liquid amine serves as its own solvent. In thisinstance the pyrrolidone carboxylic acid is added to the amine and whenall of the acid has been added, the excess solvent is removed bydistillation and the desired compound isolated, and re-crystallized frombutyl alcohol or Elemental Analysis Amine salt Empirie M.W. M.P., 0.Percent Percent Percent formula Carbon Hydrogen Nitrogen Thry. Fnd.Thry. Fnd. Thi'y. Fnd.

Betaine CmHnNzOs--- 245.3 128-130 48.97 48.83 6.99 7.02 11.42 11.31Choline ommuoinu u 232. A 51.70 49.12 8. 68 7.14 12.06 11.01 Methenaminen ,8 503--- 268.3 204 (dee) 49.24 49.31 6.76 6.66 26.11 26.23 MorpholineGammon--. 215.2 106-106 50.22 50.81 7.02 7.12 13.02 13.20 PiperazineCQHNN3O3 214.2 181-183 60.45 51.01 7.53 7.86 19.62 19.41

The appropriate amine carbonate may be used in place acetone. Morpholinepyrrolidone carboxylate obtained in this way compares in every respectwith that obtained as a result of Examples 2 and 4.

Example 6 When it is desired to administer the amine salts ofpyrrolidone carboxylic acid in therapy of humans and animals, these maybe administered tablets, capsules,

powders, granules or liquid-dose forms for oral administration orparenterally by intravenous or intramuscular injection or by slowcontinuous intravenous drip infusion. The range of daily dosage is from1 gram to 15 grams per day, depending upon the individual patientsneeds. The particular dosage-form used may then be administered toprovide the daily dosage selected for the particular patient.

Tablets are prepared by mixing the selected amine salt of pyrrolidonecarboxylic acid with a diluent in a ratio of 1 part active compound tofrom 0.25 to 9 parts of diluent. The diluent to be used may be lactose,sucrose, corn starch and potato starch. After thorough mixing, the wholeis wetted with a granulating solution, as for example, 5 percent gelatinsolution, 2 percent tragacanth solution or 1 percent acacia solution andthe wetted mass passed through a No. 16 coarse sieve. The granulatedmass is then dried and mixed with a lubricant, such as magnesiumstearate, in the amount of from 0.1 to 0.25 gram, dependent upon thesize of the batch. After thorough mixing, the granulation is compressedinto tablets of the proper size and shape. The unit dosage concentrationof active material for a tablet may be as high as 0.75 gram of activesubstance, although itwill be found preferable to utilize a smallerconcentration as for example, 500 mg. of active ingredient per tablet.

The granulation-mix prior to the addition of a lubricant as preparedabove, may be utilized for the preparation of capsules, or the pureactive ingredient may be filled directly into the capsule. In thepreparation of capsules, the amount of active ingredient which isutilized for each unit dose may range from 0.1.gram to 1.0 gram.

When it is desired to dispense the active ingredient in the form of apowder, it is mixed directly with a diluent such as sucrose, lactose,mannitol, corn starch, potato starch or mixtures of these, in a ratio offrom 1 part active ingredient and 1 part diluent to 1 part activeingredient and 14 parts diluent. The concentration of active ingredientis adjusted so that each unit dose of the powder, as for example, ateaspoonful or tablespoonful, will contain from 0.5 to 5 grams of theactive substance. Each unit dose of the powder may be taken with milk,fruit juice or any other suitable liquid.

In order to prepare granules, a preliminary mix of the active ingredientand a diluent, is formulated. The ratio of the active ingredient to thediluent is from 1 part active ingredient to one to fourteen partsdiluent. Such substances as sucrose, lactose, mannitol, corn starch,potato starch or mixtures of these, may be utilized as diluents. Thepreliminary mix is then granulated with a granulating solution such as 5percent gelatin solution, 2 percent tragacanth solution, 1 percentacacia solution and the wetted mass passed through a No. 8 coarse sieve.After the primary granulation has been dried, it is mixed with suitablecoloring and flavoring and the granulating process repeated, utilizingeither water or 40 percent (by weight) alcohol-water solution. Afterpassing. through a coarse No. 8 sieve, the granules are dried. The rangein concentration of active substance per unit dose of the granules(teaspoonful or tablespoonful) is from 0.5 to 5 grams of activeingredient.

Liquid dose forms, suitable for either oral or parenteraladministration, are prepared by the simple dissolution of i the activecompound in a pharmaceutically acceptable carrier. Thus, by the simpledissolution of the selected amine sale of pyrrolidone carboxylic acid inwater, simple syrup, alcohol, glycerine, propylene glycol, sorbitol, orcombinations of these, a liquid-preparation suitable for oraladministration results, which permits the convenient administration ofthe daily dosage requirements. The range in concentration of the activematerial in the liquid dosage form is adjusted so that the individualunit dose (teaspoonful r tablespoonful) will continue from 1 gram tograms of the active compound. In the preparation of the liquid dose formthe active ingredient is dissolved directly into the selected vehicleand suitable flavoring and coloring may be added if desired. When wateris used as the solvent for the synthesis of the active compound, thenthe reaction product need not be isolated, if a liquid dose form isintended. In this instance, the reaction mixture is concentrated underreduced pressure so that a range of from 1 gram to 5 grams per unit dose(teaspoonful or tablespoonful) results. The addition of suitableflavoring and coloring is then added to this mixture.

When it is intended to utilize the liquid dose form by parenteral means,then water-for-injection is utilized as a solvent and the formulation isprepared under aseptic conditions. The active ingredient is selected anddissolved in the water-for-injection and the solution is filteredthrough a bacterial filter. The filtered solution is then filled intoampules and sterilized by autoclaving or any other suitable technique asfor example, Tyndalization. The concentration of active ingredient percc. of injectable solution ranges from 0.1 to 5.0 grams. When aconcentrated solution is desired for addition to the continuousintravenous drip infusion, it will be found preferable to adjust theamount of active ingredient in the concentrate so that each cc. ofsolution contains at least one gram of active substance. The concentrateis then added directly to the infusing liquid for administration by slowcontinuous intravenous drip.

Example 7 When it is desired to utilize the amine salts of pyrrolidonecarboxylic acid to treat the depressed mental state of the geriatricpatient, it will be found desirable to administer a total daily dosageof from 1 gram to 15 grams of the selected active compound in aconvenient close form, as for example, capsules, tablets, powders,granules, or liquids by the oral route, or by injection of a parenteralsolution, either intramuscularly or intraveneously. The total dailydosage of the chosen compound may be divided into from one to sixindividual doses, to be administered at a frequency consistent with thepatients needs.

Example 8 In order to efiect a normalization of the elevated level ofserum gamma-globulin fraction of the blood of the alcoholic patient,choline pyrrolidone carboxylate or betaine pyrrolidone carboxylate maybe administered in a total daily dosage of from 1 gram to 15 grams. Thetotal daily dosage may be divided into from 1 to 6 unit doses of aliquid, tablet, capsule, powder or granules, to be administered by theoral route, or injected intravenously or intramuscularly or by slowcontinuous intravenous drip.

Example 9 When it is desired to achieve a psychotonic effect, then theselected amine salt of pyrrolidone carboxylic acid may be administeredas a liquid, tablet, capsule, powder or granule by the oral route, or asan intravenous or intramuscular injection by the parenteral route in atotal daily dosage of from 1 to 15 grams. The active ingredient is shownto traverse the blood-brain barrier to achieve an augmentation ofcerebro-cellular functioning.

What is claimed is:

1. A compound selected from the group consisting of betaine pyrrolidonecarboxylate, choline pyrrolidone carboxylate, methenamine pyrrolidonecarboxylate, morpholine pyrrolidone carboxylate, and piperazinepyrrolidon carboxylate. 1

2. Betaine pyrrolidone carboxylate.

3. Choline pyrrolidone carboxylate.

4. Methenamine pyrrolidone carboxylate.

5. Morpholine pyrrolidone carboxylate.

6. Piperazine pyrrolidone carboxylate.

(References on following page) References Cited by the Examiner UNITEDSTATES PATENTS Connstein 260268 Ledrut 260285 Henderson 16755 Sprague eta1. 16755 Fox 260247.2

Cusic 260247.2 Blackett et a1. 260251.5 10 Skel1y 260-326.3

10 3,002,978 10/ 1961 Bocher 260326.3 3,013,058 12/1961 Richter 260247.23,019,226 1/ 1962 Bernstein et a1. 260268 FOREIGN PATENTS No. 51M 2/1961France. No. 121M 3/1961 France.

N0.M1134 3/1962 France.

NICHOLAS S. RIZZO, Primary Examiner.

IRVING MARCUS, WALTER MODANCE, Examiners.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BETAINE PYRROLIDONECARBOXYLATE, CHOLINE PYRROLIDONE CARBOXYLATE, METHENAMINE PYRROLIDONECARBOXYLATE, MORPHOLINE PYRROLIDONE CARBOXYLATE, AND PIPERAZINEPYRROLIDONE CARBOXYLATE.
 5. MORPHOLINE PYRROLIDONE CARBOXYLATE.